Photodynamic therapy (PDT) is well known, having clinical applicability in both cancerous and non-cancerous indications. PDT involves a compound known as a “photosensitizer” which can be excited or activated in a variety of ways, including, for example, by visible or near infrared light of a specific wavelength. PDT treatment is an oxygen dependent reaction, in which the production of reactive oxygen species causes tissue damage by cellular necrosis or apoptosis. Indeed, the availability and/or generation of oxygen can influence the success of PDT.
PDT treatment involves administering a photosensitizing agent to a patient for delivery of the agent to a target tissue, illuminating the target tissue and activating the photosensitizer, which acts as a catalyst to destroy the target tissue by generating singlet oxygen. Like most catalysts, photosensitizers are not themselves destroyed during the activation process, and can thus be used repeatedly with proper activation.
PDT has become known as an effective treatment modality for various types of cancer including, lung cancer, head and neck cancer, bladder cancer, Barrett's oesophagus, and skin cancer. Non-cancerous applications include degenerative eye disorders, such as, macular degeneration, skin conditions such as, actinic keratosis, psoriasis, localized scleroderma, acne vulgaris and granuloma annulare, and inflammatory (rheumatoid arthritis) and infective disorders (e.g. dental infections, Leishmaniasis).
Research has shown that PDT for cancer provides numerous advantages over conventional therapies, such as chemotherapy and radiation, including higher efficacy with localized and specific tumour treatments, and potential for repetition of therapy without cumulative toxicity. PDT, which can be an outpatient therapy, also reduces the duration of treatment when compared to the weeks to months of radiotherapy, chemotherapy and/or prolonged hospitalization after surgery. Finally, in contrast to most conventional cancer therapies, PDT can induce immunity and thus may contribute to long-term control of abnormal cell proliferation.
Due to their high lipophilicity, delivery of photosensitizers for clinical applications can be problematic. In an attempt to overcome this challenge, various encapsulation strategies have been studied to protect the hydrophobic photosensitizer from aqueous environments.
Once such strategy involves the use of non-biodegradable nanoparticles for the delivery of photosensitizer compounds such as, ceramic (silica), gold, iron oxide and polyacrylamide nanoparticles. Such nanoparticles are not typically utilized as a means of compound delivery due to their inability to degrade and to release compounds in a controlled manner. However, given that photosensitizers are not themselves toxic to targeted cells, but instead act like catalysts to produce toxic products from non-toxic dissolved oxygen, non-biodegradable nanoparticles may be used as carriers for directed delivery of photosensitizers to target tissue. To be effective, however, non-biodegradable nanoparticles must be small enough in size to have a volume of distribution roughly equivalent to that of the photosensitizer, thereby extensively limiting compound size to a maximum allowable diameter of 100 nm, and preferably less than 50 nm.
Another strategy involves the use of biodegradable nanoparticles, which are advantageously capable of providing high compound loading, the possibility of controlling compound release and the existence of a wide variety of materials and manufacturing processes. Biodegradable nanoparticles are solid colloidal particles formed by the association of suitable polymers. It is known that the chemical composition of such polymers can be readily designed to incorporate compounds with variable degrees of hydrophobicity, molecular weight and charge. The surface properties and morphologies can also be optimized for controlled compound release kinetics and polymer degradation. For instance, attachment of site-specific moieties may enable active targeting of compounds, and modifying the surface with polymers, such as poly(ethylene glycol) and poly(ethylene oxide) may prolong circulation times. As such, biodegradable nanoparticles are known as pharmaceutically acceptable delivery vehicles for lipophilic compounds, such as, for example, photosensitizers.
Due to difficulties in applying light therapy, including the costs of the light source and variability of light application by people in their home, PDT treatment can also suffer from inadequate or inconsistent activation of photosensitizers, thereby reducing the efficacy of the clinical application. Given the essential role of oxygen in PDT therapy, it may be possible to use alternative activation methods of photosensitizers and/or oxygen production to enhance PDT treatment. For instance, increasing the availability of oxygen by, for example, the application of hydrogen peroxide may provide a synergistic effect when applied in combination with PDT treatment.
Thus, there is first a need for a compound (e.g., photosensitizer) delivery system that can incorporate the compound within the system efficiently without loss or alteration of its activity, be biodegradable and result in minimum immunogenicity. The system may further provide a selective accumulation (i.e. in therapeutic concentrations) of the compound within the diseased tissue with little or no uptake by normal/healthy surrounding cells. The system may further provide an environment for the compound to be administered parenterally (systemically or topically or in aerosol suspension) for treatment. There is also a need for a means for activating a compound (e.g. photosensitizer) that may or may not involve the use of light.